The invention is directed to compounds that are useful in treating inflammation and cardiac conditions and that contain N-containing heterocycles such as piperazine or piperidine moieties coupled to phenyl and other aryl groups. More particularly, the invention concerns compounds of this type as well as methods to treat proinflammatory and heart and kidney conditions using these and other compounds.
A large number of chronic and acute conditions have been recognized to be associated with perturbation of the inflammatory response. A large number of cytokines participate in this response, including IL-1, IL-6, IL-8 and TNF. It appears that the activity of these cytokines in the regulation of inflammation rely at least in part on the activation of an enzyme on the cell signaling pathway, a member of the MAP kinase family generally known as p38 and alternatively known as CSBP and RK. This kinase is activated by dual phosphorylation after stimulation by physiochemical stress, treatment with lipopolysaccharides or with proinflammatory cytokines such as IL-I and TNF. Therefore, inhibitors of the kinase activity of p38 are useful anti-inflammatory agents.
PCT applications WO98/06715, WO98/07425, WO98/28292 and WO 96/40143, all of which are incorporated herein by reference, describe the relationship of p38 kinase inhibitors with various disease states. As mentioned in these applications, inhibitors of p38 kinase are useful in treating a variety of diseases associated with chronic inflammation. These applications list rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, gouty arthritis and other arthritic conditions, sepsis, septic shock, endotoxic shock, Gram-negative sepsis, toxic shock syndrome, asthma, adult respiratory distress syndrome, stroke, reperfusion injury, CNS injuries such as neural trauma and ischemia, psoriasis, restenosis, cerebral malaria, chronic pulmonary inflammatory disease, silicosis, pulmonary sarcosis, bone resorption diseases such as osteoporosis, graft-versus-host reaction, Crohn""s Disease, ulcerative colitis including inflammatory bowel disease (IBD) and pyresis.
The above-referenced PCT applications disclose compounds which are p38 kinase inhibitors said to be useful in treating these disease states. These compounds are either imidazoles or are indoles substituted at the 3- or 4-position with a piperazine or piperidine ring linked through a carboxamide linkage. Additional compounds which are conjugates of piperazines with indoles are described as insecticides in WO97/26252, also incorporated herein by reference.
U.S. Pat. No. 5,719,135 describes tyrosine kinase inhibitors containing piperidine or piperazine rings linked through a methylene at position 1 of piperidine to various aromatic systems which must further contain a xcex3 lactam fused to a pyridine ring. Similar compounds are described in U.S. Pat. No. 5,663,346 and in WO96/22976. Other cyclic tyrosine kinase inhibitors are described in PCT application WO95/06032. In addition, WO94/20062 describes balanoids as protein kinase C inhibitors. The balanoid compounds contain multiple aromatic systems which include at least a ring containing at least seven members. Some of the compounds useful in the method of the present invention are known compounds.
Additional compounds which contain piperidine or piperazine linked to an indole, benzimidazole, or benztriazole ring system are disclosed in PCT publication WO99/61426 published Dec. 2, 1999; PCT publication WO00/59904 published Oct. 12, 2000, and PCT publication WO00/71535 published Nov. 30, 2000, the contents of all of which are incorporated herein by reference. Related compounds to those described herein are also set forth in PCT publication WO00/12074 published Mar. 9, 2000 and incorporated herein by reference.
The invention is directed to methods of treating inflammation generally, including specific conditions such as those described in the Background section above. The compounds of the invention have been found to inhibit p38 kinase and are thus useful in treating diseases mediated by this enzyme. These compounds also inhibit p38xcex1 preferentially as compared to their inhibition of p38xcex2 as is further discussed below.
The compounds useful in the invention are of the formula 
and the pharmaceutically acceptable salts thereof, or a pharmaceutical composition thereof,
wherein
Z is N or CR1, R1 is a noninterfering substituent,
each of X1 and X2 is a linker,
Ar1 and Ar2 are identical or different, and represent optionally substituted C1-C20 hydrocarbyl residues wherein at least one of Ar1 and Ar2 is an optionally substituted aryl group, with the proviso that when X2 is CH2 or an isostere thereof, X1 is CO or an isostere thereof, and Ar2 is optionally substituted phenyl, Ar1 is other than an optionally substituted indolyl, benzimidazolyl or benzotriazolyl substituent, and wherein said optionally substituted phenyl is not an optionally substituted indolyl, benzimidazolyl, or benzotriazolyl,
Y is a noninterfering substituent, wherein n is an integer from 0-4, and
wherein m is an integer from 0-4 and 1 is an integer from 0-3.
Preferably, the compounds useful in the invention are of the formula 
and the pharmaceutically acceptable salts thereof,
wherein Ar1 is optionally substituted furanyl, thiophenyl, phenyl system having 0, 1, or 2 heterocyclic N atoms or naphthyl system having 0, 1, 2 or 3 heterocyclic N atoms;
X1 is CO or an isostere thereof;
Y is optionally substituted alkyl (1-6C), optionally substituted aryl (6-10C), or optionally substituted arylalkyl (7-11C);
n is 0 or 1;
Z is CH or N;
X2 is CH2 or an isostere thereof; and
Ph is optionally substituted phenyl.
The optional substituents on the aryl moieties (including phenyl) include halo, nitro, optionally substituted alkyl (1-6C) or alkenyl (1-6C), CN, guanidino or CF3, as well as RCO, COOR, CONR2, SO2NR2,xe2x80x94OOCR, xe2x80x94NROCR, xe2x80x94NROCOR, NR2, OR or SR, wherein R is H or alkyl (1-6C), as well as substitution by phenyl, itself optionally substituted by the foregoing substituents. Any two substituents may form a 5-7 membered carbocyclic or heterocyclic ring subject to the proviso.
Thus, in one aspect, the invention is directed to compounds of the formulas set forth above and to pharmaceutical compositions containing them. In other aspects, the invention is directed to methods of treatment and preparation of medicaments using compounds of the formula set forth above. The invention is also directed to uses of specific classes of compounds within the genus of formula (1). In particular, the invention is related to compounds of formula (3) 
In other aspects, the invention is directed to methods to produce the compounds useful in the invention.
In particular, the invention is directed to the use of compounds of formula (3) to prepare a medicament for treatment of conditions mediated by p38xcex1 kinase or to methods of treatment of such conditions wherein the substituents in formula (3) are defined in the alternative as follows:
1. In formula (3), Ar1 is a furanyl ring system optionally substituted by noninterfering substituents other than phenyl;
X1 is CO or an isostere thereof;
Z is N or CH;
X is CH2 or an isostere thereof; and
Ph is optionally substituted phenyl.
2. In formula (3), Ar1 is a thiophene ring system optionally substituted by a noninterfering substituent, and not fused to an additional ring;
X1 is CO or an isostere thereof;
Z is N or CH;
X2 is CH2 or an isostere thereof; and
Ph is optionally substituted phenyl.
3. In formula (3), Ar1 is an optionally substituted aryl group other than optionally substituted indolyl, benzimidazolyl, or benzotriazolyl;
X1 is CO or an isostere thereof;
Z is N or CH;
X2 is CH2 or an isostere thereof; and
Ph represents optionally substituted phenyl
wherein at least one of Ar1 and Ph is substituted by at least one substituent comprising a saturated ring system optionally containing 1-2 N atoms and/or 1-2 O atoms.
4. The compound of formula (3) is a compound illustrated in FIGS. 1A-1I.